Summary (OVERALL) The introduction of antiretroviral therapy (ART) in the mid-1990's has had a dramatic impact on the natural history of HIV infection and HIV-associated nephropathy (HIVAN). While the overall mortality and the incidence of ESRD attributed to HIVAN has decreased, the incidence of all cause ESRD among HIV-infected patients has not changed and remains significantly higher than that observed in the general population. With prolonged survival and aging of the HIV population, non-AIDS complications including kidney disease have emerged as major contributors to morbidity and mortality and continue to disproportionately affect individuals of African origin. The latter can at least partially be explained by the strong association of single nucleotide polymorphisms (SNP) in APOL1 with idiopathic and HIV-associated FSGS in African- Americans, although the mechanism remains unknown. This Program Project Grant will investigate the long-term consequences of chronic HIV infection on the kidney including contribution to chronic kidney disease, critical host factors that influence that interaction as well as the role the kidney plays as a long-term, potentially latent reservoir for the virus that could drive chronic inflammation. Critical observations made in the prior funding cycle have contributed to the work proposed including the observation that HIV infection accelerates the progression of kidney disease in the setting of diabetes and that HIV completes a virus life cycle in the kidney, induces inflammation and in the kidney and can become latent in a subset of renal tubule epithelial cells. Key Inflammatory pathways induced by HIV have been defined in renal tubule epithelial cells and in podocytes providing insights for possible interventions that will be explored. New preliminary data in the HIV transgenic murine model has demonstrated an interaction between host microbiome and kidney pathogenesis. Through three highly interactive projects (and two linked RO-1s) and four essential cores, with investigators that have a strong track record of collaboration, we will explore the hypothesis that chronic infection with HIV, even under complete viral suppression, has long-term consequences in the kidney, both by promoting CKD (Project 4) and by providing a long-term reservoir for the virus that promotes chronic inflammation (Project 2 and linked RO-1) and that critical host factors influence these consequences including APOL1 variants (linked RO-1) and host microbiome (Project 3). Engineered transformed and primary cells, transgenic murine models and human samples provided by Core C with biopsy histopathology determined by the histopathology Core (B) will be used to explore the hypotheses proposed. An informatics Core (D) will provide critical and innovative analyses of in vitro and in vivo derived data sets. A multi-modality communications and data sharing plan will allow continuous review of data and sharing of experimental approaches and data to move the science forward. This PPG addresses important challenges in HIV and CKD research, including the intersection of HIV and progression of chronic diseases associated with aging, as well as the recognition that cure initiatives require a complete understanding of the implications of HIV in chronic reservoirs.